Early-stage reduction of the dendritic complexity in basolateral amygdala of a transgenic mouse model of Alzheimer's disease

Highlights

• Neuron-level, reduction of dendritic complexity in BLA of 9-month-old AD mice.

• Specific range of branch decrease in density of 6-month-old AD mice.

• 3D imaging with high resolution will provide insights into brain aging.

Abstract

Alzheimer's disease is a representative age-related neurodegenerative disease that could result in loss of memory and cognitive deficiency. However, the precise onset time of Alzheimer's disease affecting neuronal circuits and the mechanisms underlying the changes are not clearly known. To address the neuroanatomical changes during the early pathologic developing process, we acquired the neuronal morphological characterization of AD in APP/PS1 double-transgenic mice using the Micro-Optical Sectioning Tomography system. We reconstructed the neurons in 3D datasets with a resolution of 0.32 × 0.32 × 1 μm and used the Sholl method to analyze the anatomical characterization of the dendritic branches. The results showed that, similar to the progressive change in amyloid plaques, the number of dendritic branches were significantly decreased in 9-month-old mice. In addition, a distinct reduction of dendritic complexity occurred in third and fourth-order dendritic branches of 9-month-old mice, while no significant changes were identified in these parameters in 6-month-old mice. At the branch-level, the density distribution of dendritic arbors in the radial direction decreased in the range of 40–90 μm from the neuron soma in 6-month-old mice. These changes in the dendritic complexity suggest that these reductions contribute to the progressive cognitive impairment seen in APP/PS1 mice. This work may yield insights into the early changes in dendritic abnormality and its relevance to dysfunctional mechanisms of learning, memory and emotion in Alzheimer's disease.

Introduction

Alzheimer's disease (AD) is the most common age-related neurodegenerative disease, and the pathogenesis of AD has always been a popular issue in modern neuroscience research [1]. AD can be characterized by loss of memory and cognitive defects in behavioral pathology, which have been the focus of several studies regarding the mechanism and treatment of AD [2]. Although extracellular depositions of amyloid-beta peptide (Aβ) and intracellular neurofibrillary tangles (NFTs) can be found in some AD patients and animal models, clinical trials have failed to give an effective treatment to prevent, halt, or reverse AD [3]. A number of studies indicate that early intervention treatment, before the onset of cognitive symptoms, would be more effective, but the clinical onset time of AD and the mechanism underlying the changes in neuronal circuits is not clearly known [4].

Some subcortical regions are affected by deposits with the progressive development of AD in patients and transgenic animal models [5], [6]. As the main brain area controlling emotional activities and associative memories, the basolateral amygdaloid nucleus (BLA) is significantly affected showing considerable shrinkage, distortion, loss of neurons and neuronal morphological alterations [7], [8]. These dendritic abnormalities as key hallmarks in the early stages of the AD, adumbrate neuroanatomical degeneration, including dystrophic neurites, reduction of dendritic complexity and loss of dendritic spines [9].

APPswe/PS1dE9 (hereinafter, APP/PS1) double-transgenic mice express a chimeric mouse/human amyloid precursor protein (Mo/HuAPP695swe) and a mutant human presenilin 1 (PS1-dE9) both involved in neurons of the central nervous system [10]. Previous reports revealed that plaque depositions were found in the brains of the transgenic mice starting at 6 months old, while there was a reduction in the dendritic complexity of BLA at 12–14 months old [6], [11], [12]. However, the mouse model of AD displays cognitive and memory deficits at 3–8 months old [13]. The morphological integrity of neurons identifying the amygdaloid circuits was not clear with respect to the progressive changes in early stages of AD.

To address the neural changes on a large-scale, during the early pathological development of AD, we used the APP/PS1 double-transgenic mice as AD models. By combining Golgi-Cox staining with Micro-Optical Sectioning Tomography (MOST), we acquired the reconstructed projection neurons in the BLA at developmental stages of AD and examined their dendritic morphology [14], [15]. The results showed that the progressive Aβ depositions and reduction of dendritic complexity could be identified in 6- and 9-month-old mice.